The pathology of HIV is a complex, multistaged phenomenon. One of the earliest manifestations is a decline in the proliferative responses and functional activity of CD4+ T lymphocytes to stimulation with nominal antigen or antibodies to the CD3 complex. These changes may occur in asymptomatic individuals up to one year prior to selective loss of the CD4+ T cell subset that typically marks the onset of AIDS. Altered CD4+ T cell function may contribute to this by establishing a permissive environment for the development of more virulent HIV clones. Work from our own and other laboratories has shown that inhibition of T cell function can occur in response to either acute exposure to HIV-1 gene products, such as gp120, or chronic HIV-1 infection. The mechanism(s) of these effects is complex and only poorly understood. Regulation of lymphocyte proliferation and differentiation is a multistep process that integrates a cascade of activation signals. Our data indicate that both acute and chronic effects of HIV-1 result from perturbation of early events of T cell activation that include protein kinase cascades and the regulation of gene expression. The studies proposed here will define the biochemical and molecular mechanisms of HIV-1 immunomodulation, and the long term consequences of these events on immune responsiveness. The specific aims are to examine: 1.INDUCTION OF T CELL NONRESPONSIVENESS BY HIV-1 2.MOLECULAR SIGNALING OF TCR/CD3 RECEPTORS BY HIV-1 3.FUNCTION OF THE TCR/CD3 COMPLEX IN CHRONIC HIV-1 INFECTION More detailed understanding of the effector molecules and sites of action of these processes will increase our knowledge of T cell growth regulation and tolerance, and aid in the development of diagnostic and therapeutic strategies for the treatment of AIDS.